Does IQ decline with age in fragile‐X? A methodological critique

Hay, David

doi:10.1002/ajmg.1320510412

Cited by 21 publications

(18 citation statements)

References 23 publications

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“…Interestingly, Hagerman et al have pointed out that abstract reasoning and symbolic language skills are often stressed in the IQ tests of later childhood and adolescence. That is, in some IQ tests, subtests are added to the assessment battery, thereby increasing the task demands at later ages (see also Hay 1994) and thus leading to apparent declines in IQ. To avoid this problem, we believe that investigators should endeavor to administer the same set of subtests to the same individuals at each time point.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been argued that declining IQ in individuals with FXS might also be explained by inherent properties of cognitive tests, which for older children, may place greater emphasis on skills that are known to be specific weaknesses in this disorder (Hagerman et al 1989). As Hay (1994) has also pointed out, interpretation of standardized IQ data in individuals with FXS is extremely problematic because investigators have combined data from different tests, different sources and from different age-groups. This problem is compounded by the fact that most IQ tests have fewer items at the low ability levels, rendering the standardized IQ scores in individuals with FXS more imprecise and less reliable.…”

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confidence: 99%

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Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Hall

Burns

Lightbody

et al. 2008

J Abnorm Child Psychol

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Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS. KeywordsFragile X syndrome; Structural equation modeling; Intellectual functioning; IQ; FMRP Fragile X syndrome occurs in approximately 1 in every 4,000 live births and is the most common inherited form of cognitive and behavioral disability. In 1991, Verkerk and colleagues reported that a single gene on the X chromosome (locus Xq27.3), FMR1, was associated with the symptoms of FXS (Verkerk et al. 1991). Subsequent research revealed that persons with FXS had increased numbers of triplet (CGG) repeats within FMR1. In normal alleles, the CGG repeats vary from 6 to 50, whereas expansions of ~50-200 repeats are associated with the "premutation" form of the gene seen in carrier females and males. The probability of having a child with the full mutation increases as the length of the mothers' CGG repeat length increases-a phenomenon known as genetic anticipation. Larger expansions (200 to thousands) of CGG repeats are considered "full mutations" and are typically associated with excessive methylation of cytosines in the FMR1 promoter. This hallss@stanford.edu. HHS Public AccessAuthor manuscript J Abnorm Child Psychol. Author manuscript; available in PMC 2016 April 04. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript modification extinguishes transcription of the FMR1 gene into mRNA, thus stopping translation of the fragile X mental retardation protein (FMRP). FMRP plays an important role in the development of synaptic function, maturation, and plasticity during development, and possibly, on an ongoing basis throughout adult life as well (Reiss et al. 1995).Investigators have reported that individuals with FXS experience weaknesses in executi...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Hall

Burns

Lightbody

et al. 2008

J Abnorm Child Psychol

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“…However, Reiss and colleagues Freund, 1990, 1992] did not find an association between IQ and autistic behavior in males or in females [Mazzocco et al, 1997] with FXS. Some of the discrepancies noted in IQ scores may be related to the challenges of securing valid IQ scores in individuals with FXS [Dykens et al, 1989;Hay, 1994;Hooper et al, 2000;Skinner et al, 2004].…”

Section: Correlates Of Autistic Behavior In Fxsmentioning

confidence: 99%

Autistic behavior in children with fragile X syndrome: Prevalence, stability, and the impact of FMRP

Hatton

Sideris

Skinner

et al. 2006

American J of Med Genetics Pt A

336

281

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We examined autistic behavior in a cross-sectional sample of 179 children with fragile X syndrome (FXS) and a longitudinal subset of 116 children using the Childhood Autism Rating Scale (CARS) to (a) determine a prevalence of autistic behavior in FXS, (b) examine the stability of autistic ratings over time, and (c) assess the association between the fragile X mental retardation protein (FMRP) and autistic behavior. Approximately 21% of the sample of 129 children (25.9% of boys) scored at or above the cutoff for autism. CARS scores increased slowly, yet significantly, over time, and low levels of FMRP were associated with higher mean levels of autistic behavior as measured by the CARS.

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“…The most prominent clinical feature of Fragile X however, is mild to severe mental retardation. Some studies in children and young adults have found progressive cognitive decline and increased autistic features with age, although some have argued that the finding may be related to the types of testing that were performed (Hagerman et al 1989; Hay 1994; Wright-Talamante et al 1996; Hatton et al 2006). In any case, extended longitudinal studies with adult patients have not been done, leaving a critical potential gap in our information regarding performance of Fragile X patients with aging.…”

Section: Introductionmentioning

confidence: 99%

“…In any case, extended longitudinal studies with adult patients have not been done, leaving a critical potential gap in our information regarding performance of Fragile X patients with aging. Also, this issue has not been extensively examined in Fragile X animal models, where it can be studied quickly and cost effectively (Hagerman et al 1989; Hay 1994; Wright-Talamante et al, 1996; Jacquemont et al 2007). Furthermore, characterizing the effect that the loss of the protein product of FMR1 (FMRP) in aging may provide clues as to the pathophysiology of fragile X-associated tremor/ataxia syndrome (FXTAS), an age onset disease afflicting some FMR1 premutation carriers.…”

Section: Introductionmentioning

confidence: 99%

Age-dependent cognitive impairment in a Drosophila Fragile X model and its pharmacological rescue

et al. 2009

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Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.

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Does IQ decline with age in fragile‐X? A methodological critique

Cited by 21 publications

References 23 publications

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Autistic behavior in children with fragile X syndrome: Prevalence, stability, and the impact of FMRP

Age-dependent cognitive impairment in a Drosophila Fragile X model and its pharmacological rescue

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